Field of the Invention
The inventions disclosed and taught herein relate generally to combinations and methods of treating disorders in mammals, particularly humans. In particular, this invention provides combination therapies and treatment regimens for the treatment of hepatic disorders and human immunodeficiency virus (HIV) using a naturally-occurring immunostimulatory oligodeoxynucleotide and a cell-wall fraction of a gram positive bacteria.
Description of the Related Art
A traditional approach to treating hepatic disorders, as well as a number of other viral disorders in mammals, is to target the virus itself with therapy, such as with virus specific chemotherapeutic agents. An alternative approach to treating such disorders is to target the immune system of the subject (“immunotherapy”), rather than, or in addition to, targeting the virus itself. A potential benefit of immunotherapy is to provide improved efficacy by enhancing the patient's own immune response to tumors while minimizing deleterious effects to normal, healthy cells.
Bacterial DNA has immune stimulatory effects to activate B cells and natural killer cells [Tokunaga, T., et al., 1988. Jpn. J. Cancer Res. 79:682-686; Tokunaga, T., et al., 1984, JNCI 72:955-962; Messina, J. P., et al., 1991, J. Immunol. 147:1759-1764, and reviewed in Krieg, 1998, In: Applied Oligonucleotide Technology, C. A. Stein and A. M. Krieg, (Eds.), John Wiley and Sons, Inc., New York, N.Y., pp. 431-448]. The immune stimulatory effects of bacterial DNA are a result of the presence of unmethylated CpG dinucleotides in particular base contexts (CpG motifs), which are common in bacterial DNA, but methylated and underrepresented in vertebrate DNA [Krieg et al, Nature, Vol. 374, pp. 546-549 (1995); Krieg, Biochim. Biophys. Acta, 93321:1-10 (1999)]. The immune stimulatory effects of bacterial DNA can be mimicked with synthetic oligodeoxynucleotides (ODN) containing these CpG motifs (referred to interchangeably hereinbelow as “CpG ODNs” or “immunostimulatory ODNs”). Such CpG ODNs have been shown to have high stimulatory effects on a number of mammalian biological functions, inducing B cell proliferation, cytokine and immunoglobulin secretion, natural killer (NK) cell lytic activity, IFN-y secretion, and activation of dendritic cells (DCs) and other antigen presenting cells to express costimulatory molecules and secrete cytokines, especially the Th1-like cytokines that are important in promoting the development of Th1-like T cell responses. The immune stimulatory effects of native phosphodiester backbone CpG ODN are highly CpG specific in that the effects are dramatically reduced if the CpG motif is methylated, changed to a GpC, or otherwise eliminated or altered [see, Krieg, et al, Nature, Vol. 374, pp. 546-549 (1995); Hartmann, et al, 1999 Proc. Natl. Acad. Sci. USA, Vol. 96, pp. 9305-9310 (1999)].
It was previously thought that the immune stimulatory effects required the CpG motif in the context of a purine-purine-CpG-pyrimidine-pyrimidine sequence [Krieg, et al., Nature, Vol. 374, pp. 546-549 (1995); Pisetsky, J. Immunol., Vol. 156, pp. 421-423 (1996); Hacker, et al., EMBO J., Vol. 17, pp. 6230-6240 (1998); Lipford, et al., Trends in Microbiol. 6:496-500 (1998)]. However, it is now clear that mouse lymphocytes respond quite well to phosphodiester CpG motifs not in this context [Yi, et al., J. Immunol. Vol. 160, pp. 5898-5906 (1998)] and the same is true of human B cells and dendritic cells [Hartmann, et al., Proc. Natl. Acad. Sci. USA, 96, pp. 9305-10 (1999)].
One class of GpG ODN is potent for activating B cells but is relatively weak in inducing IFN-alpha and NK cell activation; this class has been termed the B class. The B class CpG oligonucleotides typically are fully stabilized and include an unmethylated CpG dinucleotide within certain preferred base contexts. See, e.g., U.S. Pat. Nos. 6,194,388; 6,214,806; 6,239,116; and 6,339,068.
It has also been shown that T cell-mediated hepatic damage plays a key role in the pathogenesis of liver diseases such as autoimmune hepatitis, viral hepatitis and acute liver failure [Becker, Y., Virus Genes, Vol. 30 (2), pp. 251-266 (2005)]. CpG-containing oligodeoxynucleotides (CpG ODN), a ligand for toll-like receptor (TLR) 9, is widely used as an immunological adjuvant, and several groups have reported on the results of their investigations of the effect of CpG ODN on T cell-mediated liver injury in murine models of hepatitis and other diseases. It has also been shown that the activation of inflammatory cells can be diminished by CpG ODN pretreatment. These results suggested that CpG ODN pretreatment protects from liver injury via inhibiting hepatocyte apoptosis, inflammation and activation of lymphocytes [Zhang, H., et al, Int. Immunopharmacol., Vol. 10(1), pp. 79-85 (2010)].
Although the individual use of CpG ODNs to induce therapeutic response hold great promise in the treatment of a number of disorders in patients, there remains a need to develop novel therapies to treat such disorders with such immunotherapeutic approaches.
The inventions disclosed and taught herein are directed to therapies and treatment regimens for the treatment of hepatic disorders, cancer, lyme disease, and/or human immunodeficiency virus (HIV), as well as compositions for such methods of treatment using a naturally-occurring immunostimulatory oligodeoxynucleotide and a cell-wall fraction of a gram positive bacteria.